TMIC-100. Astrocytes Orchestrate Sensitivity to Ferroptosis in Glioblastoma

Abstract Glioblastoma is the most aggressive primary malignant brain tumor with dismal survival. Despite surgical resection and adjuvant therapy, the tumor almost always recurs. Tumor recurrence is enriched in treatment-resistant mesenchymal-like glioblastoma stem cells (GSCs), which represent a major obstacle to treatment. GSCs are resistant to many chemotherapies and ionizing radiation; however, recent evidence suggests that they are particularly sensitive to death by lipid peroxidation, a phenomenon known as ferroptosis. However, we found that not all GBM GSCs are sensitive to ferroptosis. Here, we propose an innovative therapeutic strategy centered on eradicating these ferroptosis-resistant GSCs by targeting their metabolic dependencies. We leveraged patient-derived GSCs as well as an ex vivo GBM slice culture model to test a new therapeutic strategy and obtained in-depth insights into GSCs and the tumor microenvironment using single-nucleus RNAseq and spatial transcriptomics. We discovered that ferroptosis sensitivity requires secreted factors from tumor microenvironment astrocytes, and have identified the mechanisms by which tumor-associated astrocytes can reverse ferroptosis resistance. This multi-faceted approach offers a promising and novel avenue for combating GBM recurrence and holds potential for treating other refractory tumors.